1. 2012-2.2.2-1: Integrative systems biology
and comparative genomics for studying
human ageing and most common age-related
conditions
PARTNERS:
Donetsk National Medical University
Department of Histology, Cytology and Embryology
Department of Propaedeutics of Internal Medicine
Institute of Urgent and Recovery Surgery
Laboratory of Fundamental Research
S. Fyodorov Eye Microsurgery Federal State Institution, Moscow, Russian Federation)

2. Drugs, nutrients, lifestyle
Aging is programmed or
simply determined by
interactions between
environmental and
genetic factors

3. Cellular determinants of ageing
•Insulin/insulin-like growth factor-1 (IGF-1) • Reactive oxygen
•Fox-head transcription factors (FOXOs) • Mitochondria dysfunction
•Klotho gene • DNA damage
•HSP • Telomere attrition
•Antioxidants • Lysosomal dysfunction
•Sirtuins • Sress-ER
•Sestrins • Proteosome dysfunction

4. Tissue and organ determinants of
ageing
Key mechanisms of development: Key features:
• Changes of Autonomic innervation: • blood pressure increase
desympathization, increase sensitivity of target
cells to epinephrine, changes in vessels tone • atherosclerosis
regulation; • may contribute to myocardial infarction
• Endothelial dysfunction - deficient of NO, and stroke
decrease of cytoprotection, loss of • limiting adult stem cell life span
antiaggregation and barrier function, changes in • wound/ ulcers healing problems
angiogenesis;
• renal / cardiac sclerosis
• Dysfunction of specialized cells • Immunological ageing
• Altered epithelio-mesenchymal
interactions (reduced IGF1 and Wnt2;
increased TGFβ, ECM hyperproduction)
• Cytokine network disturbance (dendritic
cells dysfunction)

5. P
R
E
L
I Vascular Specialized cells
Connective tissue
M Endothelium cells (pigment epithelium)
I
N PG I2 NО
PEDF
A PG E2
NО EGF
ILGF
R
Y Endothelin-1
ACE bFGF
VEGF
AngII Extracellular matrix
TGFβ TGFβ
hyperproduction
S Pigment
T Endothelial epithelium
U dysfunction dysfunction
D Published: “Pathology of eye at pseudoexfolliation syndrome” – M., 2010. – 156 p.
Y Method of early diagnostics of glaucoma at pseudoexfoliation syndrome (patent of Russia №2010116856)
The pathogenesis of open-angle glaucoma with pseudoexfoliationsyndrome // Ophthalmology. – 2010. – Vol. 3. – p. 106.

6. Integrative model for early diagnostics and
prognosis
Approach for analysis
Morphology Inhibitor analysis
Immunocytochemistry (blood cells as model)
Clinical Verification Integrative analysis of Genes
symptoms Individual reactivity polymorphism
•Disease stage/degree
•Kinetics of cells •Receptors sensitivity
Functional •Cellular types and activities microRNA
•Intracellular signaling
loading tests •Chemical composition of
matrix (Phospholipases, Ca2+, eNOS, Adenilyl
Cyclese, Phosphodiesterases,
•Functional reserve Protein Kinases A, C, G)
CELLULAR AND MOLECULAR TARGETS

7. Preliminary results: diabetes mellitus. Complications
Prognosis of diabetic wound healing
Monocytes Platelets
CD 68 + Arginase iNOS Aggregation
300
240 Violation of microcirculation,
platelets
release of 5-HN, TXA2 etc
180
120
Cytokines NO
60 Induce
CD 31 + adhesion
Arachidonic acid metabolites
0
К 1 day 3 days 10 days 20 days
Endothelial dysfunction
NADPН-oxidase р38-МАРК AGEs
-Adreno- and adenosine receptors
sensitivity
ROS iNOS Са2+
AT1 receptors (X1)
-Protein kinase C hyperstimulation
α -SMA cAMP - PkА
PkА ↑↑↑ПкС
↑↑↑ПкС CGMP - PkG
- ↓ eNOS / PDE5 (X2)
Y= -0,032 × X 1 -0,0029 × X 2 + Y= -0,03 × Х1-0,082 × Х2-1,652
1,630
Ycrit=0,515
Published in : Clinical surgeryсrit =0,281 Physiological Journal, 2011.
Y . - 2009, 2010.

8. Thank you for attention